NEWER DRUGS IN CARDIOLOGY

Dr Dhirendra Singhania
Senior consultant cardiologist
Pushpanjali Crosslay Hospital
Newer drugs

• Newer Anti Anginals - Ranolazine

- Ivabradine

• Polypill
Chronic stable angina

THEN and NOW

Myocardial ischemia:
Sites of action of anti-ischemia
medication
Development of ischemia Consequences of ischemia

↑ O2 demand
• Electrical instability
• Heart rate • Myocardial dysfunction
• Blood pressure (↓ systolic function/
•
Ischemia
Preload ↑ diastolic stiffness)
• (Ca2+ overload)
Contractility

↓ O2 supply
Conventional
Ranolazine
anti-ischemic
medications Compression
of nutritive
 ß blockers blood vessels
 Nitrates
 Ca++ blockers

(Stone, 2004)
Consequences associated with
dysfunction of late sodium current

• Diseases
(eg, ischemia, heart
failure) Na+ channel

• Pathological milieu
(reactive O2 species, (Gating
mechanism
ischemic metabolites) malfunction)
• Toxins and drugs
(eg, ATX-II, etc.)

Mechanical Oxygen supply Electrical

dysfunction and demand instability

• Abnormal contraction • Increase ATP

• Early after potentials
and relaxation consumption
• ↑ diastolic tension • Beat-to-beat ΔAPD
• Decrease ATP
(↑LV wall stiffness) formation• Arrhythmias (VT)
Diastolic relaxation failure increases
oxygen consumption and reduces oxygen
supply

Increased myocardial tension during

diastole:
– Increases myocardial O2 consumption
– Compresses intramural small vessels
• Reduces myocardial blood flow

– Worsens ischemia and

angina
Ranolazine: Mechanism of action

Ischemia Ranolazine
inhibits the late inward
↑ Late INa Na current

Na+ overload

Ca2+ overload

Diastolic relaxation failure

(increased diastolic tension)
Extravascular compression
Monotherapy with ranolazine increases
exercise performance at trough and peak:
MARISA
Placebo 500 mg bid
1000 mg bid 1500 mg bid
Trough Peak
***
*** ***
560 ***
** ***
Time, sec

520 *** ***

480 *** *** ***
*** *** *** ***
440
*** ***
400 **
Exercise Time Time to 1- Exercise Time Time to 1-
duration to angina mm duration to angina mm
ST ST
depression depression

n=175,
**p <0.01 vs placebo; ***p <0.001 vs. placebo

Chaitman et al JACC 2004;43:1375

Combination regimen of ranolazine
with:
► Atenolol 50 mg qd, or
► Diltiazem 120 mg qd, or
► Amlodipine 5 mg qd (CARISA)

Placebo 750 mg bid 1000 mg bid

* *
150 Trough Peak
Change from baseline, sec

** **
* *
*** ***
* **
100

50
Exercise Time Time to 1-mm Exercise Time Time to 1-mm
duration to angina ST depression duration to angina ST depression

n=791
*p <0.05; **p ≤0.01; ***p ≤0.001 vs placebo.

Chaitman et al. JAMA 2004;291:309

Effect of ranolazine in patients with
refractory angina despite
maximum amlodipine therapy: ERICA

Angina episodes/week NTG consumption/week

p=0.18

Number of NTGs consumed/week

Number of angina episodes/week

p=0.48
5.5
p=0.028 p=0.014
6 5.0
4.5
5 4.0
3.5
4
3.0

3 2.5
2.0
2 1.5
1.0
1
0.5
0 0.0
Amlodipine Amlodipine Amlodipine Amlodipine
+ + + +
Placebo Ranolazine Placebo Ranolazine

Baseline On placebo On ranolazine

Stone et al. Circulation 2005;112:II-748

 Effect of ranolazine in patients with
refractory angina despite
maximum amlodipine therapy: ERICA

Subgroup analyses
Consistent treatment effect of ranolazine across the subgroups
analyzed:

Long-Acting Nitrate (LAN) users vs non-LAN users

(n=254 vs 310)
Men vs women
(n=407 vs 158)
Patients aged <65 years vs ≥65 years
(n=234 vs 331)

Stone et al. Circulation 2005;112:II-748

 MERLIN TIMI-36
(n=6500)
UA/NSTEMI
CP <48h, ST-Dep or +cTn, or DM, or TRS 3
Standard therapy

RANDOMIZE (1:1)
Ranolazine Double-blind Placebo
IV to PO Matched IV/PO
Holter at enrollment x 7 days

Follow-up Follow-up visits:

Q4 mo Day 14, month 4,
(Avg 8-12 mo) Q4 months
Primary end point
Duration Cardiovascular death, MI
Event-driven Final Visit or recurrent ischemia

Additional endpoints: Exercise performance, extent of myocardial injury,

angina questionnaire, quality of life, arrhythmia
 Ranolazine: Adverse events

Placebo Ranolazine
(n=552) (n=835)
Constipation (%) 2 8
Nausea (%) 1 4
Dizziness (%) 2 5
Headache (%) 2 3
Pts discontinuing Rx (%) 3 6
Ranolazine prolongs the QTc an average of about 6
msec.
(No episode of torsades de pointes has been observed)
Ranolazine

• Oral administration-peak plasma conc. 2-5hrs

• 75%excretedin urine, 25%-feces
• Metabolized rapidly and extensively in liver
&intestine.
• Terminal half life 7hrs
• Steady state is generally achieved within 3 days
of bid dosing.
DRUG INTERACTIONS
Summary of Ranolazine drug-drug interactions

Drug Pharmacokinetic/ Administration Adjustments

Pharmacodynamic Interaction

Cimetidine No increase in ranolazine plasma No ranolazine dose adjustment is required

concentration
Ketoconazole 3.2-fold increase in average Ranolazine should not be used during
ranolazine steady-state (SS) ketoconazole treatment
plasma concentration
Digoxin 1.5 –fold increase in digoxin The dose of digoxin may have to be reduced
plasma concentration when ranolazine is co-administered; no
ranolazine dose adjustment is needed.

Diltiazem 1.8- to 2.3-fold increase in average Ranolazine should not be used during
ranolazine SS plasma treatment with diltiazem
concentration
Rifampin Ranolazine plasma concentration Co-administration with ranolazine should be
reduced 95% avoided
Paroxetine 1.2-fold increase in average No ranolazine dose adjustment required
ranolazine SS plasma
concentration
Cont.......
Drug Pharmacokinetic/
Pharmacodynamic Interaction
Simvastatin Approximate 2-fold increase in Simvastatin dose may have to
simvastatin and its active be reduced
metabolite plasma concentration
Verapamil About 2-fold increase in Do not co-administer
ranolazine SS plasma verapamil and ranolazine
concentration
warfarin No significant pharmacokinetic No warfarin dose adjustment
effects required

CYP3A inhibitors Increase in ranolazine plasma Should not be co-

(potent or concentration administered with ranolazine
moderately potent
CYP2D6 substrates Ranolazine and/or its metabolites Lower doses of CYP2D6
(eg, tricyclic partially inhibit CP2D6 substrates may be required in
antidepressants, the presence of ranolazine
antipsychotics)
Cont…….
 Drug Pharmacokinetic/ Administration Adjustments
Pharmacodynamic Interaction
P-glycoprotein In vitro studies suggest The dose of p-glycoprotein
substrates ranolazine is an inhibitor of p- substrates may have to be
glycoprotein reduced when co-
administered with
ranolazine
P-glycoprotein May increase absorption of Caution should be
inhibitors (eg, ranolazine exercised
cyclosporine,
ritonavir)
CYP3A and likely May decrease ranolazine Co-administration with
P-gp inducers plasma concentration to ranolazine should be
subtherapeutic levels avoided.
PATIENTS SHOULD BE
ADVISED:

• That Ranolazine will not abate an acute angina episode to

inform their physician of any other medications when taken
concurrently with Ranolazine, including over-the-counter
medications.
• That Ranolazine is only for patients not responding adequately
to other antianginal drugs.
• That Ranolazine may produce changes in the electrocardiogram
(QTc interval prolongation), congenital long QT syndrome, or
proarrhythmic conditions such as hypokalemia.
• That Ranolazine should be avoided in patients receiving drugs
that prolong the QTc interval such as class la (eg, quinidine) or
Class III (eg, dofetilide, sotalol antiarrhythemic agents,
erythromycin, and certain antipsychotics (eg, Thioridazine,
Ziprasidone)
Cont…….
• avoided in patients receiving drugs that are potent or
moderately potent inhibitors of CYP3A, including, for example,
ketoconazole, HIV protease inhibitors, macrolide antibiotics,
diltiazem, and verapamil.
• That grapefruit juice or grapefruit products should be avoided
when taking Ranolazine.
• That Ranolazine should generally be avoided in patients with
mild, moderate, or severe liver impairment.
• That Ranolazine should genrally be avoided in patients with
severe renal impairment.
• That doses of Ranolazine higher than 1000mg twice a day
should not be used.
• That if a dose of Ranolazine is missed, the usual dose should
be taken at the next scheduled time. The next dose should not
be doubled.
Cont.......
• That Ranolazine may be taken with or without meals.
• That Ranolazine tablets whould be swallowed whole and
not crushed, broken , or chewed to contact their
physician if they expeience palpitations or fainting spells
while taking Ranolazine.
• That Ranolazine may cause dizziness and
lightheadedness; therefore, patients should know how
they react to this drug before they operate an
automobile, or machinery, or engag in activities requiring
mental alertness or coordination. Se tablets).
Chronic stable angina

THEN and NOW

Elevated resting heart rate is
associated with higher mortality in CAD

•The CASS registry: n=24 913; 14.1-year follow-up

•Adjusted survival curves •Adjusted survival curves for

for overall mortality cardiovascular mortality
•1.0 •1.0

•0.9 •0.9

•Cumulative survival
•Cumulative survival

•0.8 •P<0.0001 •0.8

•0.7 •P<0.0001
•0.7

•0.6 •0.6
•=<62
•=>83 bpm
•0.5 •0.5
•0 •5 •10 •15 •20 •0 •5 •10 •15 •20
•Years after enrolment •Years after enrolment

•Diaz A, et al. Eur Heart J. 2005;26:867-874.

Heart rate reduction is associated with
a decrease of post-MI cardiac deaths

•Meta-regression of 12 controlled studies

•2.0

•1.0
•Odds ratio

•0.5

•0.2

•β-Blockers •P<0.00042

•0.1 •Calcium channel blockers

•0 •-5 •-10 •-15 •-20

•Absolute heart rate reduction (bpm)

•Cucherat Ml. Eur Heart J. 2007;28:3012-3019.

IVABRADINE

• Ivabradine acts by reducing the heart rate in a

mechanism different from beta blockers and
calcium channel blockers, two commonly
prescribed antianginal drugs .
• Ivabradine acts on the If (f is for "funny ion
current, which is highly expressed in the
sinoatrial node.
• If is a mixed Na+–K+ inward current activated by
hyperpolarization and modulated by the
autonomic nervous system
 IIVABRADINE

• Most important ionic currents for regulating pacemaker

activity in the sinoatrial (SA) node.
• Ivabradine selectively inhibits the pacemaker If current
in a dose-dependent manner. Blocking this channel
reduces cardiac pacemaker activity, slowing the heart
rate and allowing more time for blood to flow to the
myocardium.
• dose of 5 mg twice daily is recommended initially, with
increase to 7.5 mg if necessary and tolerated. in the
elderly, the manufacturer recommends a starting dose of
2.5 mg.
 IVABRADINE

INITIATIVE: Study design

International Trial on the Treatment of Angina with Ivabradine vs. Atenolol

Ivabradine 10 mg bid
5 mg bid
(n = 317) Placebo

Ivabradine 7.5 mg bid

5 mg bid
(n = 315) Placebo

Placebo
2–7 days 7 days 4 weeks 12 weeks 2 weeks
Washout Run-in
Atenolol 100 mg
50 mg 50 mg
(n = 307) 25 mg
Selection ET

Inclusion ET ET* ET*

ET = exercise test (treadmill)

*ET at trough and 4 hours post-dose Tardif J-C et al. Eur Heart J. 2005;26:2529-36.
 INITIATIVE

INITIATIVE: Effects of ivabradine vs β-blockade

on primary outcome

95 P < 0.001 for noninferiority vs atenolol

91.7
(both ivabradine doses)
90
86.8
Change in
85
exercise
duration 78.8
80
(seconds)

75

0
Atenolol Ivabradine Ivabradine
100 mg 7.5 mg bid 10 mg bid
(n = 286) (n = 300) (n = 298)

Patients completing trial Tardif J-C et al. Eur Heart J. 2005;26:2529-36.

 INITIATIVE

INITIATIVE: Summary

• Ivabradine 7.5 mg bid and 10 mg bid were noninferior to atenolol

100 mg as measured by
– Total exercise duration
– Time to limiting angina, angina onset, and 1 mm ST
• Most common adverse events were transient visual symptoms,
mainly increased brightness in limited areas
• Sinus bradycardia occurred in 2.2% (ivabradine 7.5 mg),
5.4% (ivabradine 10 mg), and 4.3% (atenolol) of patients

If current inhibition may be as effective as β-blockade

in treatment of stable angina

Tardif J-C et al. Eur Heart J. 2005;26:2529-36.

Ivabradine

• highly water soluble,rapidly absorbed,peak plasma

levels in 1 hr in fasting condition.
• Taken up with meals
• Extensively metabolizedby liver and gut by oxidation
through cytochrome CYP3A4.
• Effective half life 11hrs
• Contraindications- hypersensitivity, bradycardia,
sss, cardiogenic shock, AMI, severe hepatic
insufficiency, severe hypotension.
• Commonest side effect luminous phenomena
 Ivabradine shows efficacy, tolerability in
diabetics with stable CAD
13 November 2009

MedWire News: Ivabradine is effective for preventing angina in patients

with diabetes mellitus and stable coronary artery disease (CAD), and has
no impact on glucose metabolism, an analysis of clinical trial data
shows.

The study supports a potential role for ivabradine as an alternative to beta blockers in the
treatment of stable angina, say the study authors writing in the American Journal of
Cardiology.
Ivabradine is a specific heart-rate-lowering antianginal agent that inhibits the If current,
the primary modulator of spontaneous diastolic depolarization in the sinoatrial node.
The drug has been evaluated in a clinical development program involving
approximately 3000 patients with stable CAD, most of whom had angina.
 Medwire news contd.

• As in non-diabetic individuals, ivabradine treatment in diabetic patients was

associated with an approximately 15% reduction in resting heart rate and an
improvement in exercise tolerance measures, including total exercise
duration, time to onset of myocardial ischemia, and time to onset of angina.

Ivabradine therapy in diabetics was also associated with a reduction in the

frequency of angina attacks but without any increase in rates of sinus
bradycardia or visual disturbances (both known to be related to the action of
ivabradine). Furthermore, ivabradine had no adverse impact on glucose
metabolism or other safety/tolerability outcomes.

“Ivabridine is effective in patients with diabetes mellitus and angina and is not
associated with particular safety concerns or adverse effects on glucose metabolism
in this population. Therefore, ivabradine represents an attractive alternative to beta-
blockers.”

Am J Cardiol 2009; Advance online publication

The concept and the appeal of
Polypill

• Aspirin, β-blockers, angiotensin-converting-enzyme

inhibitors, and statins reduce cardiovascular disease.

• One combination pill including all the above drugs could potentially
reduce recurrent vascular events in people with cardiovascular
disease by about 75%

Yusuf S. Two decades of progress in preventing cardiovascular disease. Lancet 2002; 360: 2–3.
The concept and the appeal of
Polypill-compliance benefits

• Adherence to treatment is poor even among those who have experienced a CVD
event and non-adherence is associated with worse outcomes

• For primary prevention, adherence to treatment is an even greater challenge than for
those who have had a major event

– Convincing people who feel well, that they need lifestyle change or lifelong drug
treatment requires high quality information and Communication

• The polypill could fit well into more modern medical systems, in which large
proportions of patients with risk factors are untreated

• Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U, for the EUROASPIRE Study Group. Cardiovascular prevention guidelines in daily practice: a comparison of EUROASPIRE I, II, and III
surveys in eight European countries. Lancet 2009; 373: 929–40.
• Ref: http://www.nice.org.uk/nicemedia/pdf/CG67FullGuideline1.pdf
Polypill and Cardiovascular
Prevention

• A strategy to reduce cardiovascular disease by more than

80%. (N.J. Wald, M.R. Law, BMJ 2003)

“Overall, the evidence suggests that fixed-dose combination pills and unit-of-
use packaging are likely to improve adherence”
J Connor et al. Bulletin WHO December 2004
“It is strongly recommended that a research agenda should be established
to produce and test FDC products for secondary prevention of heart attack
and stroke to improve adherence and prevent mortality and morbidity”
Kaplan Laining. Priority Medicines for Europe and the World 2004

“This expert panel believes that the concept of CP shows sufficient

promise to justify the additional scientific testing of its potential public
health applications”
Combination Pharmacotherapy and Public Health WG
The challenges

• Could the Polycap be formulated?

• If so, what molecule should it contain from each class of drug?
• What strength of each molecule should be used?
• Would it be too large to swallow?
• Will it be a stable formulation?
• Will these drugs interact with each other inside the Polycap?
• Do we need 3 antihypertensives?
• Will nearly healthy people take this Polycap?
• Will the individual drugs in the Polycap work?
• Will the Polycap be safe? (Adverse Events)
Can it reduce risk factors and CVD substantially?
Formulating a polypill-Is it a
mere
“add this to that”?
• Stability testing
• Pharmacokinetic analysis
– Bioavailability of drugs when given as polycap vs those when given individually

• Efficacy
– To see for the individual effects and contributions of each component to the
overall efficacy

• Drug interactions
• Safety
TIPS : The Indian Polycap Study
TIPS: Components of the
Polycap

Antiplatelet ASA 100 mg/d

Statin Simvastatin 20 mg/d

ACE-Inhibitors Ramipril 5 mg/d

Beta-blocker Atenolol 50 mg/d

Diuretic Hydrochlorothiazide 12.5 mg/d

TIPS: Composition of the
eight comparator groups

1) ASP: Aspirin (100 mg)

2) T: Thiazide (12.5 mg)

3) T + R: Thiazide (12.5mg) Ramipril (5mg)

4) T + At: Thiazide (12.5mg) Atenolol (50mg)

5) R + At: Ramipril (5mg) Atenolol (50 mg)

6) T + R + At: Thiazide (5mg) Ramipril (5 mg) Atenolol (50 mg)

7) T+R+At+ASA: Above (6) + ASA100 mg

8) S Simvastatin 20 mg
TIPS: Study Design

• Randomized and double blind

• Polycap vs. 8 other formulations
• Superiority and inferiority comparisons
• Active treatment for 12 weeks
• Wash out for 4 weeks
• Impact on BP, HR, lipids, urine thromboxane B2
• Safety and tolerability.
• Parallel PK study.
Combinations and comparisons

Composition of comparators Type of comparison

Thiazide 12.5mg + Ramipril 5mg + Non-inferiority

Atenolol 50mg (BP)
Thiazide 12.5mg + Ramipril 5mg + Non-inferiority
Atenolol 50mg + Aspirin 100mg (BP, Platelet inhibition)
Non-inferiority
Aspirin 100mg
(Platelet inhibition )
Non-inferiority
Simvastatin 20mg
(lipid lowering)
Hydrochlorothiazide 12.5mg Superiority (BP)
Thiazide12.5mg+Ramipril 5mg Superiority (BP)
Thiazide12.5mg +Atenolol 50 mg Superiority (BP)
Ramipril 5 mg + Atenolol 50 mg Superiority (BP)
 TIPS: Primary Objectives

Whether the Polycap is equivalent :

1. In reducing BP when compared with its components

containing 3 BP lowering drugs (HCTZ, atenolol, ramipril)
2. In reducing HR when compared with atenolol
3. In modifying lipids when compared with simvastatin alone
4. In suppressing urine thromboxane B2 vs ASA alone
5. In its rates of adverse event when compared with its
equivalent components
TIPS: Secondary Objectives

• Whether Polycap is superior in reducing BP compared to

its components containing
– One BP lowering drug (thiazide) or
– Two BP lowering drugs
• HCTZ + Ramipril
• HCTZ + Atenolol
• Ramipril + Atenolol
Power for Non-Inferiority Comparisons
for the Key Outcomes

Comparison of Non-
1-sided type
Outcomes Treatment Inferiority Power
1 error
Arms Margin (SD)
BP: Diastolic BP P vs TRAt or 2 (6) mm Hg 0.025 94%
TRAtAs
Lipids (LDL chol) P vs S 0.155 (0.46) 0.025 97%
mmol/L
Antiplatelet therapy P vs TRAtAs 60 (181) 0.025 96%
(Urinary
Thromboxane B2)
TIPS: Statistcal methods

• Intention to treat.
• All post- rand variables utilized by a repeated
measures approach.
• Results are baseline and “control” group
subtracted.
• When 12 week BP, HR or lipids were missing,
we used earlier measures resulting in 96% BP
data and 91% lipid data.
TIPS: Organization
Sponsor - Cadila Pharma,
India

Indian Coordinating Center International Coordinating Center

Population Health Research Institute
St. John’s Medical College, Research HHS and McMaster University, Hamilton, Canada
Institute,

Steering committee

53 Centers in India
TIPS: Target Population

Inclusion Criteria:
• Age 45 to 80 years
• At least one CV risk factor
• Hypertension (SBP > 140 ≤ 159; DBP > 90 ≤ 100Hg, but treated)
• Diabetes mellitus (on one oral drug / diet)
• Smoker > 5 years
• Raised WHR
• Abnormal lipids (LDL 130-175mg/dl)
• Informed consent
Exclusion Criteria:
• On study meds and cannot be stopped
• 2 or more BP lowering meds
• LDL >175mg/dl
• Abnormal renal function (Cr>2.0mg/dl or K+>5.5 mEq/L)
• Previous CVD or CHF
TIPS: Study Flow

Screening
(stabilization and baseline assessments)
 3 weeks
Randomization (BP, HR, urine, lipids)
 7 to 10 days (BP, HR)
 4 weeks (BP, HR)
 8 weeks (BP, HR)
 12 weeks (BP, HR, urine, lipids)
Washout  16 weeks (BP, HR)
Final treatment allocation

2053
As - 205
Polycap - 412 T - 205
TR - 209

TAt - 207

RA - 205

TAR - 204
TAtRAs - 204

S - 202
Flow Chart of the Study and
Data Completeness

No. randomized = 2053

No. final visit = 86%
No. with post rand HR/BP = 96%
No with post rand lipids at anytime = 91% (81%)*

*At scheduled end

Inclusion criteria

Total patients randomized 2053

HTN 1297(63.2)
Type-2 DM 696(33.9)
Current smoker>5yrs 240(11.7)
High WHR 1501(73.1)
Abnormal lipids 676(32.9)
TIPS: Selected Baseline
Characteristics

Characteristics Overall
N 2053
Age 54.0 (7.9)
BMI 26.3 (4.5)
Heart rate (beats/min) 80.1 (10.7)
Diabetes 33.9%
Current Smoker 13.4%
Females 43.9%
Calcium Channel Blockers 21.7%
TIPS: Selected Baseline
Characteristics

Characteristics Overall
N 2053
Systolic BP (mmHg) 134.4 (12.3)
Diastolic BP (mmHg) 85.0 (8.1)
Total Cholesterol (mmol/d) 4.7 (0.9)
LDL (mmol/L) 3.0 (0.8)
HDL (mmol/L) 1.1 (0.3)
Triglycerides (mmol/L) 1.9 (1.2)
ApoB 0.9 (0.2)
ApoA 1.2 (0.2)
Results
Mean Changes in BP (95% CI)
vs 0 Drugs

Reductions (mmHg)
SYS DIA
1 BP lowering -2.2 -1.3
2 BP lowering -4.7 -3.6
3 BP lowering -6.9 -5.0
Polycap -7.4 -5.6
 C h a n g e in s ittin g S B P ( 9 5 % C I) C h a n g e in s ittin g S B P ( 9 5 % C I)

-14 -1 2 -1 0 -8 -6 -4 -2 0 -14 -12 -10 -8 -6 -4 -2 0

As

No
As,S

Anti-ht
T

T
TR
TAt
RAt

Treatment
Treatment

TR,TAt,RAt
TRAt
TRAtAs
Change in SBP/DBP

TRAt,TRAtAs
S
P

Polycap
C h a n g e in s ittin g D B P ( 9 5 % C I) C h a n g e in s ittin g D B P ( 9 5 % C I)

-14 -12 -10 -8 -6 -4 -2 0 -14 -12 -10 -8 -6 -4 -2 0

As

As ,S
T

T
TR
TAt
RAt

Treatment
Treatment

TR,TAt,RAt
TRAt
TRAtAs

TRAt,TRAtAs
S
P

Poly cap
Change in SBP DBP
As,S As,S
T T
TR,TAt,RAt TR,TAt,RAt
TRAt,TRAtAs,P TRAt,TRAtAs,P
0

0
Change in Sitting DBP
Change in Sitting SBP
-5

-5
-10

-10

Rand W2 W4 W8 W 12 W 16 Rand W2 W4 W8 W 12 W 16
(End of Trt) (End of Trt)
Visit Visit
Impact of Atenolol arms vs Polycap
on Heart Rate

Reduction in HR CI P

Polycap -7.0 (-6.3 to -7.7) 0.001

Other Atenolol arms -7.0 (-6.2 to 7.9) 0.001

Non Atenolol arms 0.0 (-0.84 to 0.85) 0.99

Polycap/Other atenolol vs non-atenolol arms <<0.0001

 Effect on Heart Rate
By baseline HR(<81 vs >=81)
2
0
-2
Change in Sitting HR(95% CI)

-4
-6
-8
-10

- + - + - +

Non-Atenolol TAt,RAt,TRAt,TRAtAs Polycap

Impact on LDL

Mean CI %
Simvastatin : -0.83 mmol -0.94 to -0.74 27.7%
Polycap : -0.70 mmol -0.78 to -0.64 23.3%

Differences: -0.13 mmol (-0.25 to -0.01) 4.4%

Differences vs both simvastatin arms compared to non-statin p<0.001

Effect not clinically significant

LDL change with Polycap vs Simvastatin p=0.04

Parallel impact on ApoB: Simv: -0.21 mmol/L vs Polycap : -0.18 mmol/L

(Diff of 0.03 mmol; p=0.06).
 Effect on LDL
0.0
Change in LDL(95% CI)

-0.4
-0.8

As T TR TAt RAt TRAt TRAtAs S P

Treatment
 Change in L

-1.0
Change in LDL by Baseline LDL and Diabetic
Status - + - + - +
Non-Statin Simvastatin Polycap

By Diabetic status(No vs Yes)

0.0
Change in LDL(95% CI)

-0.5
-1.0

- + - + - +
Non-Statin Simvastatin Polycap
TIPS: Impact of Various Treatments
on Urinary Thromboxane B2

Mean CI

ASA alone -388.0 (-453 to -322)

P <0.001 vs
3 BP lowering -389.2 (-457 to -321)
drugs + ASA baseline

Polycap -322.3 (-369 to 276)

Selected safety parameters (%)

Ov As T TR TAt RA TRA TR S P
AtAs

Dizziness 4.5 4.9 3.9 1.9 2.9 5.4 5.4 5.4 2.5 6.3

Cough 3.8 1.5 3.4 7.2 0.5 3.9 3.9 5.9 1.0 5.3

Fatigue 1.8 1.0 2.0 1.4 1.9 2.0 3.4 0.5 2.0 1.7

Bradycardia 0.2 0 0 0 1.0 0 0.5 0.5 0 0.2

Cr>50% Rnd 8.3 9.3 6.8 7.7 9.7 7.3 7.4 10.3 7.9 8.5

Potasm>5.5 5.3 5.9 4.4 5.3 4.8 5.9 7.4 6.9 3.5 4.4

SGPT>2 ULN 1.0 0.5 0.5 3.3 1.9 1.0 0 0.5 1.5 0.5
Reasons for drug discontinuations
Temporary or Permanent (%)

Ov As T TR TAt RAt TRA TR S P

AtAs

Soc/ refused 21.8 22.9 22.0 21.5 16.4 22.0 27.0 24.5 23.8 19.2

Dizz/ HoT 3.4 2.9 3.4 1.0 1.9 4.4 4.4 4.4 3.0 4.4

Gastr/ dysp 1.4 1.5 1.0 2.4 1.0 1.5 1.0 1.5 1.5 1.2

Hyperkalem 0.2 0 0 0 0 0.5 0.5 0.5 0 0.2

Cough 0.9 0.5 0.5 2.4 0 1.0 0.5 1.5 0 1.5

Drug intol (other) 0.5 0.5 0.5 1.0 0 0.5 0 1.5 0 0.5

Bradycard 0.2 0 0 0 0.5 0.5 0 0.5 0 0.5

Other 6.3 6.8 4.9 4.8 6.3 7.8 7.8 7.4 3.5 7.0

Total 29.8 28.3 28.0 27.8 24.2 31.2 35.8 33.8 28.2 29.9
TIPS: Reasons for Permanent
Discontinuation of Study Drug

Polycap: Reasons for Permanent Discontinuation

30

25

20
Other Reasons
Percent

15 Specific Reasons
Social Reasons/Refusals
10

0
As,S,T TR,Tat,RAt TRAt TRAtAs Polycap
Estimated reductions in CHD/Stroke of a
Polycap in Those With Average Risk Factor
Levels
% Relative Reduction

Reduction in CHD Stroke

Risk Factors
LDL-C
(mmol/L) Est (Simv 20) 0.80 27% 8%

DBP
(mmHg) Est (3, ½ dose) 5.7 24% 33%

Platelet
function Est (ASA 100 Similar 32%* 16%
mg)
Combined Est - 62% 48%

*RCTs suggest a smaller benefit

TIPS: Strengths

• 9 Arms
– Ability to understand impact of specific components of Polycap
• Comprehensive evaluation of
– Safety (glucose, SGPT, clinical) and
– Efficacy (BP, HR, lipids, TBx2)
• Provides substantial information for the development of a clinically
useful Polycap
TIPS: Summary

In those with average risk factor levels,

• The Polycap is similar to the added effects of each of its 3 BP
lowering components.
• There is greater BP lowering with incremental components.
• ASA does not interfere with the BP lowering effects.
• The Polycap reduces LDL to a slightly lower extent compared to
simvastatin alone
• The Polycap lowers thromboxane B2 to a similar extent as aspirin
alone.
• There are no significant drug-drug interactions
• The Polycap is well tolerated.
• The Polycap could potentially reduce CVD risk by about half.
Impact of Polycap
Advantages of the Polycap

• Improved compliance of both physicians and patients

• Decreased costs
• Increased access: Non-physicians prescribe /OTC and
physicians deal with resistant or complex situations and
adverse effects
• A basis for promoting prudent lifestyle.
• Potential large reductions in vascular events
Who could benefit from the
Polycap?

• Populations: Those with vascular disease? those at hi

risk( eg DM, etc)? those over the age of 55?
• Settings:
• Mid and low income countries or all?
• Physician based or non-physician based?
• Prescription or OTC?
 Impact of Polycap in India

• 70% of the Indians reside in the rural areas

• CVD - the leading cause of mortality, accounting for at least 32% of all
deaths.
• 51% of all CV deaths occurred in patients <70 years of age 1
• Prevalence of CHD was estimated to be 4.8% (95% CI, 4.1 to 5.)
• The prevalence of CeVD was estimated at 2.0% (95% CI, 1.5 to 2.4) 1

Rohina Joshi, Clara K. Chow,P. Krishnam Raju et al ; Fatal and Nonfatal Cardiovascular Disease and the Use of Therapies for Secondary
Prevention in a Rural Region of India
Suboptimal management of CVD

• Among individuals with either diagnosis,

– 14% (95% CI, 10 to 18) reported taking aspirin,
– 41% (95% CI, 36 to 47) took a blood pressure-lowering medication
– Only 5% (95% CI, 3 to 7) reported using a cholesterol-lowering medication 1

• Polycap can be a safe and comprehensive option to optimize the

treatment

Rohina Joshi, Clara K. Chow,P. Krishnam Raju et al ; Fatal and Nonfatal Cardiovascular Disease and the Use of Therapies for Secondary
Prevention in a Rural Region of India
“Why does the Polypill make everybody
mad?”

• Makes prevention very easy: Challenges the established

mantra of “tailoring” drugs and doses to the individual.
• Challenges the need for physicians to be involved in
prevention.
• Costs of prevention will SUBSTANTIALLY decrease:
challenges the dominance of BIG PHARMA.
• Anti-establishment.
 IVABRADINE

INITIATIVE: Study design

International Trial on the Treatment of Angina with Ivabradine vs. Atenolol

Ivabradine 10 mg bid
5 mg bid
(n = 317) Placebo

Ivabradine 7.5 mg bid

5 mg bid
(n = 315) Placebo

Placebo
2–7 days 7 days 4 weeks 12 weeks 2 weeks
Washout Run-in
Atenolol 100 mg
50 mg 50 mg
(n = 307) 25 mg
Selection ET

Inclusion ET ET* ET*

ET = exercise test (treadmill)

*ET at trough and 4 hours post-dose Tardif J-C et al. Eur Heart J. 2005;26:2529-36.
 INITIATIVE

INITIATIVE: Effects of ivabradine vs β-blockade

on primary outcome

95 P < 0.001 for noninferiority vs atenolol

91.7
(both ivabradine doses)
90
86.8
Change in
85
exercise
duration 78.8
80
(seconds)

75

0
Atenolol Ivabradine Ivabradine
100 mg 7.5 mg bid 10 mg bid
(n = 286) (n = 300) (n = 298)

Patients completing trial Tardif J-C et al. Eur Heart J. 2005;26:2529-36.

 INITIATIVE

INITIATIVE: Summary

• Ivabradine 7.5 mg bid and 10 mg bid were noninferior to atenolol

100 mg as measured by
– Total exercise duration
– Time to limiting angina, angina onset, and 1 mm ST
• Most common adverse events were transient visual symptoms,
mainly increased brightness in limited areas
• Sinus bradycardia occurred in 2.2% (ivabradine 7.5 mg),
5.4% (ivabradine 10 mg), and 4.3% (atenolol) of patients

If current inhibition may be as effective as β-blockade

in treatment of stable angina

Tardif J-C et al. Eur Heart J. 2005;26:2529-36.

 Ivabradine shows efficacy, tolerability in
diabetics with stable CAD
13 November 2009

MedWire News: Ivabradine is effective for preventing angina in patients

with diabetes mellitus and stable coronary artery disease (CAD), and has
no impact on glucose metabolism, an analysis of clinical trial data
shows.

The study supports a potential role for ivabradine as an alternative to beta blockers in the
treatment of stable angina, say the study authors writing in the American Journal of
Cardiology.
Ivabradine is a specific heart-rate-lowering antianginal agent that inhibits the If current,
the primary modulator of spontaneous diastolic depolarization in the sinoatrial node.
The drug has been evaluated in a clinical development program involving
approximately 3000 patients with stable CAD, most of whom had angina.
 Medwire news contd.

• As in non-diabetic individuals, ivabradine treatment in diabetic patients was

associated with an approximately 15% reduction in resting heart rate and an
improvement in exercise tolerance measures, including total exercise
duration, time to onset of myocardial ischemia, and time to onset of angina.

Ivabradine therapy in diabetics was also associated with a reduction in the

frequency of angina attacks but without any increase in rates of sinus
bradycardia or visual disturbances (both known to be related to the action of
ivabradine). Furthermore, ivabradine had no adverse impact on glucose
metabolism or other safety/tolerability outcomes.

“Ivabridine is effective in patients with diabetes mellitus and angina and is not
associated with particular safety concerns or adverse effects on glucose metabolism
in this population. Therefore, ivabradine represents an attractive alternative to beta-
blockers.”

Am J Cardiol 2009; Advance online publication

Effect of ranolazine in patients with
refractory angina despite
maximum amlodipine therapy: ERICA

Subgroup analyses: Frequency of angina

≤4.5 angina >4.5 angina ≤4.5 angina >4.5 angina
episodes/week episodes/week episodes/week episodes/week
6 p=0.029 p<0.001
p<0.001 p=0.57
30
5

Change from Baseline

Number/Wk

in SAQ Score
4
20
3 p=0.036

p=0.28
2
10

0 0

Angina NTG Angina NTG Angina frequency domain

frequency use frequency Use (Seattle Angina Questionnaire)

Placebo + Amlodipine Ranolazine + Amlodipine

Stone et al. Circulation 2005;112:II-748